Increased circulatory levels of fractalkine (CX3CL1) are associated with inflammatory chemokines and cytokines in individuals with type-2 diabetes

Abstract

BackgroundFractalkine (CX3CL1) is involved in the development of numerous inflammatory conditions including metabolic diseases. However, changes in the circulatory fractalkine levels in type-2 diabetes (T2D) and their relationship with inflammatory chemokines/cytokines remain unclear. The aim of the study was to determine the T2D-associated modulations in plasma fractalkine levels and investigate their relationship with circulatory chemokines/cytokines.MethodsA total of 47 plasma samples were collected from 23 T2D and 24 non-diabetic individuals selected over a wide range of body mass index (BMI). Clinical metabolic parameters were determined using standard commercial kits. Fractalkine and chemokines/cytokines were measured using Luminex X-MAP® technology. C-reactive protein (CRP) was measured by ELISA. The data were compared using unpaired t-test and the dependence between two variables was assessed by Pearson’s correlation coefficient (r).ResultsPlasma fractalkine levels were significantly higher (P = 0.005) in T2D patients (166 ± 14.22 pg/ml) as compared with non-diabetics (118 ± 8.90 pg/ml). In T2D patients, plasma fractalkine levels correlated positively (P ≤ 0.05) with inflammatory chemokines/cytokines including CCL3 (r = 0.52), CCL4 (r = 0.85), CCL11 (r = 0.51), CXCL1 (r = 0.67), G-CSF (r = 0.91), IFN-α2 (r = 0.97), IL-17A (r = 0.79), IL-1β (r = 0.97), IL-12P70 (r = 0.90), TNF-α (r = 0.58), and IL-6 (r = 0.60). In non-diabetic individuals, fractalkine levels correlated (P ≤ 0.05) with those of CCL4 (r = 0.49), IL-1β (r = 0.73), IL-12P70 (r = 0.41), and TNF-α (r = 0.50). Notably, plasma fractalkine levels in T2D patients associated with systemic inflammation (CRP) (r = 0.65, P = 0.02).ConclusionsThe altered plasma fractalkine levels associate differentially with inflammatory chemokines/cytokines in T2D patients which may have implications for T2D immunopathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40200-017-0297-3) contains supplementary material, which is available to authorized users.

Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus

“…The inflammatory response is one of the main underlying molecular mechanisms involved in the pathophysiology of insulin resistance, DM, and its related complications [53,103,104]. There is growing evidence that low-grade chronic inflammation is involved in the pathophysiology of insulin resistance and DM [104][105][106][107][108][109][110]. These deleterious processes can also initiate other pathophysiologic mechanisms of DM such as impairment of IST and beta-cell dysfunction [53,107].…”

“…These effects were also reported for other inflammatory mediators such as TNF-α and Nf-κb which can modulate IRS-1 serine phosphorylation at various sites and thereby impair normal IST [112][113][114]. Higher levels of monocytes and macrophage activity and circulatory mediators such as CX3CL1 (fractalkine), CRP (C-reactive protein), TNF-α (tumor necrosis factor-alpha), IL-(interleukin-) 6, IL-1β, IL-18, MCP-1 (monocyte chemoattractant protein-1), resistin, PAI-1 (plasminogen activator inhibitor-1), E-selectin, and IFN-γ (interferon-gamma) have been detected in patients with diabetes [104,[106][107][108][109][110]. Therefore, ameliorating these inflammatory processes may be a therapeutic option for the management of diabetes [105,115,116].…”

“…Increase inflammatory responses which in turn induces insulin resistance in several pathways [104,[106][107][108][109] Mitochondrial dysfunction Impairs normal function of mitochondria thereby reduces cellular capacity for glucose uptake by GLUT-4 transporters [100,[130][131][132][133]135] PPAR-γ: peroxisome proliferator-activated receptor gamma; IST: insulin signaling transduction; CEB/Ps: CCAAT enhancer-binding proteins; HIF-1α: hypoxia-inducible factors alpha; MEF2: myocyte enhancer factor 2; IRS-1: insulin receptor substrate-1; Akt: protein kinase B; IKK-β: inhibitor of nuclear factor kappa B; GSK-3: glycogen synthase kinase 3; AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; p38 MAPK: p38 mitogen-activated protein kinases. 7 Oxidative Medicine and Cellular Longevity preventive protocols for subjects who are at high risk of insulin resistance, i.e., obese subjects and their place in current therapeutics need to be determined.…”

Enhanced Adipose Expression of Interferon Regulatory Factor (IRF)-5 Associates with the Signatures of Metabolic Inflammation in Diabetic Obese Patients

“…The signature inflammatory chemokines that are implicated with metabolic inflammation belong to the subfamilies CXC (e.g., 5,8,9), CC (e.g., CCL-2, 3,4,5,7,19), and CX3C (e.g., CX3CL-1). Notably, elevated levels of these chemokines in obesity/T2D have been linked to adipose tissue inflammation and insulin resistance [20][21][22].…”

Adipose tissue expression of CCL19 chemokine is positively associated with insulin resistance

“…In obesity, pro-inflammatory chemokines/cytokines are considered to trigger systemic and local inflammatory changes leading to insulin resistance, T2D, and related complications. [18][19][20][21][22] The chemokine CCL19 has been associated with a number of inflammatory conditions including multiple sclerosis 23 , atherosclerosis, 24 and rheumatoid arthritis . 25 In the present study, we show that CCL19 gene expression was significantly elevated in the adipose tissues of obese non-diabetic individuals as compared with lean individuals and the changes correlated with BMI.…”